Novel thereapeutics to treat genetic disorders

Period of Performance: 04/15/2003 - 12/31/2003


Phase 2 SBIR

Recipient Firm

PTC Therapeutics, Inc.
South Plainfield, NJ 07080
Principal Investigator


DESCRIPTION (provided by applicant): Many human diseases are caused by mutations that result in the loss of an important gene product. A significant number of these are caused by "non-sense" mutations that prevent the synthesis of a full-length protein and result in loss of function. The importance of the effects of non-sense codons to human health is illustrated by the identification of a growing number of inherited diseases in which the respective mRNAs have been shown to contain non-sense mutations. Non-sense mutations cause approximately 15-30 percent of the individual cases of nearly 1800 different inherited diseases. Interestingly, for many diseases, such as cystic fibrosis, in which only one percent or less of the functional protein is produced, patients suffer serious disease symptoms, but boosting expression to only five percent of normal levels can greatly reduce the severity or eliminate the disease. In addition, a remarkably large number of the most common forms of cancers result from non-sense mutations in regulatory genes. Correcting non-sense mutations in the regulatory genes to permit synthesis of the respective proteins should also cause death of the cancer cells. Both molecular and genetic results demonstrate that it is possible to suppress the effects of premature termination codons to produce functional protein. We have identified compounds that suppress non-sense mutations in both in vitro and in cell-based assays. Based on these results, the aims of this proposal are to further characterize these compounds by monitoring their effect on specificity of non-sense codon suppression (UGA vs. UAA vs. UAG) and toxicity, initiate structure-activity studies around these scaffolds, perform a high throughput screen to identify compounds that exhibit greater potency and efficacy toward the UAG and UAA non-sense codons; and develop and analytical method to detect the compounds in mouse serum to prepare for pharmacokinetic studies.